Daratumumab combinations: what can we learn?

Kastritis, Efstathios

doi:10.1182/blood-2017-07-793349

Cited by 4 publications

(3 citation statements)

References 8 publications

(7 reference statements)

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“…More recently, Krejcik and colleagues (14,15) have shown that daratumumab depletes CD38 þve immune regulatory cells, which promoted the expansion of TCR-related T lymphocytes. Although these findings are surprising because they suggest that daratumumab is capable of depleting cells with considerable lower levels of CD38, they also indicate that drugs able to enhance the immune system may be preferred partners to combine with anti-CD38 mAbs (16). Accordingly, both preclinical (11,13,17,18) and clinical data have confirmed the efficacy of daratumumab in combination with lenalidomide (19,20) or pomalidomide (21).…”

Section: Introductionmentioning

confidence: 99%

The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma

Moreno

Pérez

Zabaleta

et al. 2019

Clinical Cancer Research

163

167

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Purpose: Knowledge about the mechanism of action (MoA) of monoclonal antibodies (mAb) is required to understand which patients with multiple myeloma (MM) benefit the most from a given mAb, alone or in combination therapy. Although there is considerable research about daratumumab, knowledge about other anti-CD38 mAbs remains scarce.Experimental Design: We performed a comprehensive analysis of the MoA of isatuximab.Results: Isatuximab induces internalization of CD38 but not its significant release from MM cell surface. In addition, we uncovered an association between levels of CD38 expression and different MoA: (i) Isatuximab was unable to induce direct apoptosis on MM cells with CD38 levels closer to those in patients with MM, (ii) isatuximab sensitized CD38 hi MM cells to bortezomib plus dexamethasone in the presence of stroma, (iii) antibody-dependent cellular cytotoxicity (ADCC) was triggered by CD38 lo and CD38 hi tumor plasma cells (PC), (iv) antibody-dependent cellular phagocytosis (ADCP) was triggered only by CD38 hi MM cells, whereas (v) complementdependent cytotoxicity could be triggered in less than half of the patient samples (those with elevated levels of CD38). Furthermore, we showed that isatuximab depletes CD38 hi B-lymphocyte precursors and natural killer (NK) lymphocytes ex vivo-the latter through activation followed by exhaustion and eventually phagocytosis.Conclusions: This study provides a framework to understand response determinants in patients treated with isatuximab based on the number of MoA triggered by CD38 levels of expression, and for the design of effective combinations aimed at capitalizing disrupted tumor-stroma cell protection, augmenting NK lymphocyte-mediated ADCC, or facilitating ADCP in CD38 lo MM patients.

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Section: Introductionmentioning

confidence: 99%

The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma

Moreno

Pérez

Zabaleta

et al. 2019

Clinical Cancer Research

163

167

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“…Knowledge of how to optimise DARA usage has largely been obtained from clinical trial observations. Kastritis et al, 12 not unreasonably, proposed that early anti-CD38 when a patient's immune system is perhaps more competent may be crucial, and this notion is supported by trial findings. In POLLUX, a phase 3 study comparing DARA-Lenalidomide(R)-dexamethasone(d) (DRd) versus Rd in RRMM patients with at least one prior LOT, only those patients who had received one LOT achieved superior rates of MRD negativity.…”

Section: Experience With Dara In Combination With Other Agentsmentioning

confidence: 90%

Putting the best foot forward when treating newly diagnosed multiple myeloma

Lim

Spencer

2023

Internal Medicine Journal

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Multiple myeloma (MM) remains an incurable disease. In Australia, patients receive sequential lines of novel agent (NA)‐based lines of therapy (LOTs), including proteasome inhibitors, immunomodulatory drugs and CD38‐targeting monoclonal antibodies within the constraints of the pharmaceutical benefits scheme. We propose that induction with a quadruplet incorporating all three drug classes and dexamethasone at diagnosis is the best approach to gain disease control.

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“…Notably, daratumumab can be integrated into other effective treatment protocols, even for patients who have undergone extensive prior therapy. 10 However, it is rational to use short course of daratumumab as re-induction therapy under such circumstance, as prolonged therapy may not increase response rate. In our study, we discontinued the daratumumab therapy after failure of first single infusion, as daratumumab was not provided as compassionate use.…”

mentioning

confidence: 99%

FLT‐3 mutation maybe an inferior predictor of daratumumab therapy in acute myeloid leukemia patients relapsed after allogeneic stem cell transplantation

Xue,

Huang,

Zhang

et al. 2024

Int J Lab Hematology

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Despite significant advancements in reducing non-relapse mortality, relapse persists as the principal cause of treatment failure. Up to 50% of patients with acute myeloid leukemia (AML) ultimately experience relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT), contingent upon disease status and unique characteristics. 1 Moreover, the prognosis for AML patients who relapse post-allo-HSCT is notably grim, with 2-year survival rates consistently falling below 20%, irrespective of the choice of salvage therapy. 2 Conventional re-induction chemotherapy followed by donor lymphocyte infusion (DLI) and/or performing second allo-HSCT depends on the fitness of patients. 3 Despite concerns about graft-versus-host disease (GVHD), the 100-day complete remission (CR) rate post DLI was only 20% in those subjects. 3 Apart from DLI, a second allo-HSCT was used in many institutes. A study of EBMT on second allo-HSCT uncovered a 2-year overall survival (OS) ranging from 23.3% to 36.4% as using different donors for the second allo-HSCT (HSCT2). It is noteworthy that achieving CR prior to HSCT2 is correlated with enhanced OS following the procedure. The attainment of CR prior to

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Daratumumab combinations: what can we learn?

Cited by 4 publications

References 8 publications

The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma

The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma

Putting the best foot forward when treating newly diagnosed multiple myeloma

FLT‐3 mutation maybe an inferior predictor of daratumumab therapy in acute myeloid leukemia patients relapsed after allogeneic stem cell transplantation

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